DE2727323C2 - - Google Patents

Description

The object of the invention results from the above Claims.

Elliot et al (Nature (1974), 248, 710) reported the isolation of the insecticide (1R, cis) -3- (2,2-dibromovinyl) -2,2-dimethylcyclopropane-carboxylic acid (S) - α- cyano -3-phenoxybenzyl ester by crystallization from the mixture of the two diastereomers by esterification of (1R, cis) -3- (2,2-dibromovinyl) -2,2-dimethylcyclopropane-carboxylic acid with racemic α- cyano-3-phenoxybenzyl -alcohol was obtained. The corresponding mixture of dichlorovinyl compounds was also prepared (Elliot et al, Pesticide Sci (1975), 6, 537), but the component corresponding to the above dibromovinyl compound was not isolated. It could be assumed that this dichlorovinyl derivative is also a very powerful insecticide. It was therefore desirable to isolate the isolated dichlorovinyldiastereoisomers, namely (S) - α- cyano and (R) - α- cyano-3-phenoxybenzyl- (1R, cis) -3- (2,2-dichlorovinyl) -2, To produce 2-dimethylcyclopropane carboxylate for testing as insecticides.

Preliminary testing of the mixture of diastereoisomers, namely an oil, indicated that separation by physical methods would be difficult. Of course, the most straightforward method of making the two isomers would be to esterify the cyclopropane carboxylic acid with the two enantiomers of α- cyano-3-phenoxybenzyl alcohol. The (R) form of the latter compound was prepared by Elliot et al (Nature (1974), 248, 710) by asymmetric addition of hydrogen cyanide to 3-phenoxybenzaldehyde in the presence of the enzyme D-oxynitrilase. Separation of a cyanohydrin by the usual separation techniques, for example via a diastereomeric precursor, was not achieved. The conditions necessary for the release of the cyanohydrin from the diastereomeric precursor are also likely to racemize the cyanohydrin. For example, it is known that optically active benzaldehyde cyanohydrin is already racemizing under extremely mild conditions.

It will be apparent to those skilled in the art that in the present invention Compounds the carbon atom which is the carboxamido group carries, substituted by four different atoms or groups and thus represents an optically asymmetrical center, d. H. So that the compounds come in two isomeric forms can exist which have the (R) - or (S) configuration. Also in the cyclopropane ring two further optically active centers exist, leading to isomers Forms give rise. So there are eight in total stereoisomeric forms possible. It should be noted that the scope of the invention extends to all individual isomers of the compounds according to the invention and also on mixtures, including racemate.

Specific examples that are typical of compounds of the invention are as follows:
(1R, 3R) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropane-carboxylic acid- (S) - α- carboxamido-3-phenoxybenzyl ester,
(1R, 3R) -3- (2,2-dibromovinyl) -2,2-dimethylcyclopropane-carboxylic acid- (S) - α- carboxamido-3-phenoxybenzyl ester
and the corresponding (R) - α- carboxamido compounds.

The method according to the invention is expediently used for Production of the cyclopropane carboxylic acid esters according to the invention carried out by that the mandelic acid amides of the formula III in a suitable Dissolves solvent in the presence of a base, the Solvent itself can be the base (such as pyridine), and that then a solution of the carboxylic acid halide to the solution Formula II in a suitable solvent, such as. B. one  Hydrocarbon solvents, for example benzene or Toluene, at a temperature in the range of -5 to + 30 ° C, preferably at room temperature. Although the reaction accelerated by the application of heat , but it’s often enough, just that Let the reaction proceed at room temperature. The product can be isolated and cleaned using conventional techniques.

Optically active cyclopropane carboxylic acid esters according to the invention can be produced are achieved through the joint implementation of an optically active carboxylic acid halide of the general formula II with an optically active mandelic acid amide general formula III or by reacting one of these optically active compounds with a racemate of the other reactant and subsequent Separation of the diastereoisomeric isomers by using the Difference in solubility, for example by fractional Crystallization.

The (S) -isomer of a mandelic acid amide of the formula III could also be used the racemic form of a carboxylic acid halide of the general formula II (for example the (±) -cis form of a compound of formula II) implemented to form a pair of diastereomers, which for convenience is referred to as (+) (S) and (-) (S) could be, and these could then be used a fractional crystallization technique.

As already stated, the cyclopropane carboxylic acid esters according to the invention are suitable as intermediates in the production of insecticides. They are particularly suitable for the production of partially or completely separate optical isomeric forms of these insecticides. These insecticidal products have the formula

You can by dehydrating the new invention Cyclopropanecarboxylic acid ester can be obtained.

A useful dehydrating agent is a phosphorus oxyhalide, such as B. phosphorus oxychloride. This stage of the process is expediently carried out in that a solution of the Oxyhalide in a suitable solvent, such as. B. a chlorinated hydrocarbon solvent, for example Methylene dichloride, for a period of approximately 30 minutes to about 30 hours with a solution of the cyclopropane carboxylic acid ester general formula I in a suitable solvent, such as. B. pyridine, at a temperature in the range of -20 to + 50 ° C, preferably in the range of -10 to approximately + 20 ° C in contact brings.

The dehydration process can be used to: Racemates of the formula I in racemates of the nitriles of the formula IV or it can also be used to convert cyclopropanecarboxylic acid esters of the formula I in the (R) or (S) configuration in the corresponding isomers of the nitriles of the formula IV convince the stereochemical configuration the optically active centers are preserved. So that means, the conversion of carboxamido to cyano proceeds without racemization or inversion or loss of optical purity. The process is therefore very well suited for production individual stereochemical isomer of the compounds of formula IV.

For example, (1R, 3R) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropane-carboxylic acid (S) - α- cyano-3-phenoxybenzyl ester made from (1R, 3R) -3- (2, 2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylic acid- (S) - α- carboxamido-3-phenoxybenzyl ester can be prepared.

Other compounds that can be prepared from the corresponding carboxamidoester by the dehydration process are the following:
(1R, 3R) -3- (2,2-dibromovinyl) -2,2-dimethylcyclopropanecarboxylic acid- (S) - α -cyano-3-phenoxybenzyl ester
as well as the corresponding (R) - α- cyano compounds.

As a result, the production of raw materials described.

Preparation of racemic 3-phenoxymandelic acid.

A mixture of 208 g of 3-phenoxybenzaldehyde cyanohydrin, 600 ml Ethanol and 400 ml of concentrated hydrochloric acid was on for 24 h Kept at room temperature, after which it was evaporated under was concentrated under reduced pressure. 500 ml of 2N sodium hydroxide solution were added to the residue and the mixture was Heated to 80 ° C for 1 h, cooled and concentrated with 250 ml Hydrochloric acid added, whereupon the mixture obtained another Heated to 80 ° C for one hour. The volatile part was through Evaporate under reduced pressure, and the residue was with a solution of 60 g of sodium bicarbonate in 60 g of water touched. The aqueous solution became of the undissolved oil decanted, stirred with activated carbon and filtered, and the filtrate was acidified with hydrochloric acid. The failed solid was collected by filtration and dried. It was racemic 3-phenoxymandelic acid, mp 131 ° C., obtained.  

Separation of racemic 3-phenoxymandelic acid.

21.0 g (1 - (-) - α- methylbenzylamine was added to a solution of 67.0 g of racemic 3-phenoxymandelic acid in 700 ml of isopropyl alcohol, and the mixture was kept at room temperature for 24 hours. The precipitated solid was collected by filtration (the filtrate was saved - see below) and recrystallized twice from 200 ml of isopropyl alcohol to give the 1 - (-) - α- methylbenzylammonium salt of (S) -3-phenoxymandelic acid, mp 153 ° C. This was then obtained with a A mixture of 150 ml of diethyl ether and 25 ml of 5N hydrochloric acid was shaken, the ether layer was separated off, washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation of the ether under reduced pressure. A residue of solid (S) -3-phenoxymandelic acid, Mp 110-112 ° C, [ α ] + 85 ° (C, 1.5, methanol).

The isopropyl alcohol solution obtained as a filtrate in the above process was concentrated to a volume of 50 ml by evaporation under reduced pressure. This concentrate was then shaken with 150 ml of 2N hydrochloric acid and the resulting solid precipitate was collected by filtration. This solid (impure [R] -3-phenoxymandelic acid) was dissolved in 400 ml of isopropyl alcohol, and then 170 g of d - (+) - α- methylbenzylamine was added to the solution. After the mixture had been kept at room temperature for 24 h, the precipitated solid was collected by filtration and recrystallized twice from 200 ml of isopropyl alcohol, the d - (+) - α - methylbenzylammonium salt of (R) -3-phenoxymandelic acid, mp 154 ° C. , was obtained. Free (R) -3-phenoxymandelic acid was obtained from this salt by treatment in the manner described above for the isolation of the (S) isomer. The (R) isomer had mp 112 ° C, [ α ] -84 ° (C, 1.0 methanol).

Preparation of (S) -3-phenoxymandelic acid amide

13.0 g of (S) -3-phenoxymandelic acid was added to a solution of 15.0 g of dry hydrogen chloride in 100 ml of methanol, and the resulting solution was kept at room temperature for 24 hours, after which the volatile portion was evaporated. Methyl (S) -3-phenoxymandelic acid was obtained as a residual oil. This was then added to 20 ml of liquid ammonia in a pressure vessel, which was then sealed. The temperature of the mixture is then allowed to rise to room temperature over 24 hours. The container was then opened to evaporate excess ammonia. The remaining material was stirred with water and the solid was collected by filtration and recrystallized from 70 ml of benzene. Impure (S) -3-phenoxymandelic acid amide, mp 93 ° C., [ α ] + 25.4 ° (C, 2.0, methanol) (approximately 80% optically pure) was obtained.

The optically pure material was made by the following procedure receive:

A suspension of 7.5 g of the impure (S) -3-phenoxymandelic acid amide in a mixture of 150 ml of benzene and 6 ml of n-butanol was stirred at 25 ° C. for 30 minutes. The undissolved solid was separated by filtration and the filtrate was evaporated. The residue was recrystallized from benzene. Optically pure (S) -3-phenoxymandelic acid amide, mp 94 ° C., [ α ] + 30 ° (C, 2.0, methanol) was obtained.

Another optically pure (S) -3-phenoxymandelic acid amide was obtained by Wie obtained repetition of the above cleaning process, the undissolved solid was used, which is derived from the benzene / farewell to n-butanol mixture.  

The invention is illustrated by the following examples explained.

Example 1

This example illustrates the preparation of (1R, 3R) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropane-carboxylic acid (S) - α -carboxamido-3-phenoxybenzyl ester.

A solution of 0.45 g (1R, 3R) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropane-carboxylic acid chloride in 2.0 ml of benzene was added at 5 ° C to a solution of 0.5 g ( S) -3-phenoxymandelic acid amide in 1.0 ml of pyridine was added and the mixture was kept at room temperature for 24 hours. After this time the mixture was acidified with dilute hydrochloric acid, the benzene layer separated, washed with water and with aqueous sodium bicarbonate solution, dried and concentrated by evaporation of the benzene under reduced pressure. The remaining oil was treated with 10 ml of cyclohexane, and the precipitated solid was collected by filtration and dried. (1R, 3R) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropane-carboxylic acid- (S) - α- carboxamido-3-phenoxybenzyl ester, mp 131 ° C., was obtained.

Example 2

This example also illustrates the preparation of (1R, 3R) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropane-carboxylic acid (S) - α- carboxamido-3-phenoxybenyl ester.

A solution of 0.44 g of (1R, 3R) -3- (2,2-dichlorovinyl) -2,2-dimethylcylopropane-carboxylic acid chloride in 2.0 ml of benzene became a solution of 0.5 g of racemic 3-phenoxymandelic acid amide in 1.0 ml pyridine added at 5 ° C. The mixture was kept at room temperature for 24 hours and then acidified with dilute hydrochloric acid. The benzene layer was separated and washed with aqueous sodium bicarbonate solution. After concentration of the benzene solution by evaporation under reduced pressure to a volume of 1.0 ml, 3.0 ml of cyclohexane was added, and the mixture was allowed to stand at room temperature. A solid precipitated (mp 124 ° C.). This was collected by filtration and recrystallized from a mixture of benzene and cyclohexane. This gave (1R, 3R) - 3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropane-carboxylic acid (S) - α- carboxamido-3-phenoxybenzyl ester, mp 131 ° C., which was obtained with the product of previous example was identical.

The benzene / cyclohexane mother liquors contained impure (1R, 3R) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropane-carboxylic acid (R) - α- carboxamido-3-phenoxybenzyl ester.

Example 3

The procedure of the previous example was used to (1R, 3R) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylic acid- (S) - α- carboxamido-3-phenoxybenzyl ester, mp 131 ° C., which was identical to the product of the previous example, from 0.65 g racemic cis-3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropane-carboxylic acid chloride and 0.5 g (S) -3-phenoxymandelic acid amide. The benzene / cyclohexane mother liquors contained impure (1S, 3R) -3- (2,2-dichlorovinyl) - 2,2-dimethylcyclopropane-carboxylic acid (S) - a- carboxamidoester.

The preparation of (1R, 3R) -3- (2,2-dichlorovinyl) - 2,2-dimethylcyclopropane-carboxylic acid (S) - α- cyano-3-phenoxybenzyl ester is described below.

A solution of 0.33 g of phosphorus oxychloride in 1.0 ml of methylene dichloride was added dropwise over a period of 5 minutes to a solution of 0.5 g (1R, 3R) -3- (2,2-dichlorovinyl) -2,2- Dimethylcyclopropane-carboxylic acid (S) - α- carboxamido-3-phenoxybenzyl ester in 1.5 ml of pyridine was added while the temperature was kept at -5 ° C. The mixture was then stirred at 0 ° C for 1 h, after which it was diluted with benzene and poured into dilute hydrochloric acid. The benzene layer was separated, washed with water and with aqueous sodium bicarbonate solution and dried and concentrated by evaporating the benzene, leaving a residue of (1R, 3R) -3- (2,2-dichlorovinyl) - 2,2-dimethylcyclopropane-carboxylic acid- ( S) - α- cyano-3-phenoxybenzyl ester, mp 54 ° C., was obtained, which when recrystallized from petroleum ether gave a pure product, mp 57 ° C.

Claims (5)

1. Cyclopropanecarboxylic acid esters of the general formula where X is chlorine or bromine. 2. A process for the preparation of the cyclopropanecarboxylic acid ester according to claim 1, characterized in that a cyclopropanecarboxylic acid halide of the general formula where Q is halogen, with 3-phenoxymandelic acid amide of the formula if appropriate in the presence of a base. 3. (1R, 3R) -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropane-carboxylic acid- (S) - α- carboxamido-3-phenoxybenzyl ester 4. (1R, 3R) -3- (2,2-dibromovinyl) -2,2-dimethylcyclopropane-carboxylic acid- (S) - α- carboxamido-3-phenoxybenzyl ester 5. Further embodiment of the method according to claim 2 for the preparation of the compounds according to claim 3 and 4, characterized in that either
(a) reacting the racemic (±) -cis acid (in the form of the acid halide) with (S) -3-phenyoxymandelic acid amide or
(b) reacting (1R, 3R) acid (in the form of the acid halide) with racemic 3-phenoxymandelic acid amide,
followed by separation of the diastereoisomers by fractional crystallization.